A striking feature of many cell signaling pathways is the utilization of multiple structurally similar ligands to convey distinct types of information. Our long term goal is to understand how signals from related ligands are interpreted and integrated in the receiving cell. In Drosophila two members of the Bone Morphogenetic Protein (BMP) family of secreted growth factors, Screw (Scw) and Decapentaplegic (Dpp), are required for specification of dorsal embryonic cell fates. Dpp is obligately required in all dorsal cells, while Scw functions primarily to potential Dpp signaling. Recent experiments focusing on receptor-ligand specificity suggest a potential mechanism by which Scw modulates Dpp signaling and the receiving cell integrates inputs from both ligands. The two ligands act primarily through independent type I receptors. Saxophone (Sax) transduces the Scw signal, while Thick veins (Tkv) mediates the response to Dpp. Interestingly, a constitutively active form of Sax does not signal in the absence of Tkv. Simultaneous activation of both Sax and Tkv results in a strong synergistic response that appears to be essential for the establishment of the complete range of dorsal cell fates in the embryo (Nguyen et al., 1998). In this proposal we will use biochemical and molecular genetic approaches to investigate the basis for synergistic signaling by the BMP type I receptors. The specific aims of this proposal are: I. To determine if Sax potentiates Tkv signaling by activation of a common downstream SMAD. II. To understand the structural basis for the functional and specificity differences between Sax and Tkv. III. To study the specificity of receptor-ligand interactions and the formation of higher order complexes between Sax and Tkv. BMPs are required for axial patterning and growth during embryonic development in a range of organisms including worms, flies, frogs, mice and humans. Despite the evolutionary distance, fundamental aspects of the BMP signaling pathway show remarkable conservation from flies to human. Since defects in BMP and TGF-beta signaling are known to cause human diseases and birth defects, the results from our studies are likely to have broad applications.